tbuckley/cabot-search huggingface dataset:
Risk reclassification of endometrial cancer according to molecular profiling: UK single centre experience.
Authors: Narda Kebaier Ep Chaabouni, Katherine Vroobel, Ayoma Attygalle, Paula Proszek, Susan Lalondrelle, Alexandra Taylor, Angela Joy George
Journal: Journal of Clinical Oncology (2023)

e17628 Background: Endometrial cancer (EC) ranks second among gynaecological malignancies worldwide. Traditionally, adjuvant treatment recommendation was based on risk stratification based on clinicopathological data. The Cancer Genome Atlas (TCGA) defined four distinct and prognostically significant molecular subgroups. Recent international guidelines recommend integrating molecular classification into risk stratification. The aim of our study was to evaluate the distribution of molecular groups in our population and its impact on treatment decision. Methods: Retrospective cohort study including all newly diagnosed endometrial cancer cases treated at the Royal Marsden Hospital between July 2020 and May 2022. Tumour specimens underwent next generation sequencing (NGS) of a two hundred gene panel including POLD1, POLE; MMR proteins and TP53; concordance for the latter two assessed also by immunohistochemistry (IHC). Risk stratification according to ESMO guidelines and following molecular classification was reviewed for each case and its potential impact on treatment decision. Results: 121 patients were included. POLE mutated tumours comprised 14 cases (11.6%), MSI hypermutated 24 cases (19.8 %), copy number high 36 cases (29.8%), copy number low 45 cases (37.2%) and 2 cases (1.6%) where classified as NOS (not otherwise specified). According to clinicopathological data, 39 tumours were categorised as low risk, 14 tumours as intermediate risk, 15 tumours as high-intermediate risk, 39 tumours as high risk and 14 were advanced/metastatic. According to final prognostic group when molecular profile was integrated 8.3 % (n = 10) of cases were reclassified: 8 cases were down staged (2 high, 3 high-intermediate, 3 intermediate) to low-risk category due to POLE mutations. 2 cases were upstaged from high-intermediate to high-risk category (copy number high tumours). There were no shifts noted in the low risk (based on clinicopathological data) prognostic group. One further case in the high-risk category (stage III, gr3 endometrioid tumour with substantial LVSI) was found to be POLE mutated and may be reclassified as low risk. For the 10 cases that were reclassified, adjuvant treatment recommendations may have been adjusted according to the most recent ESMO guidelines. Conclusions: Molecular classification refines traditional risk classification of EC and may change treatment recommendation in a non-negligible proportion of patients. Efforts should be made to implement molecular analysis in routine clinical practice to guide appropriate treatment.
A phase II trial of ponatinib and blinatumomab in adults with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL).
Authors: Nicholas James Short, Elias Jabbour, Nitin Jain, Walid Macaron, Xuelin Huang, Guillermo Montalban-Bravo, Tapan M. Kadia, Naval Guastad Daver, Fadi Haddad, Marianne Zoghbi, Cedric Christophe Nasnas, Lewis Fady Nasr, Ejiroghene Mayor, Wuliamatu Deen, Jennifer Thankachan, Christopher Loiselle, Rebecca Garris, Marina Konopleva, Farhad Ravandi, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2023)

e19013 Background: Ponatinib and blinatumomab are both active in Ph+ ALL. A combination of these agents may lead to durable remissions when given in the frontline setting and may eliminate the need for chemotherapy or stem cell transplant (SCT). Methods: In this phase II study, patients (pts) with newly diagnosed Ph+ ALL received up to 5 cycles of blinatumomab in combination with ponatinib, followed by ponatinib maintenance for at least 5 years. Ponatinib 30mg daily was given during cycle 1 and decreased to 15mg daily once a complete molecular response (CMR) was achieved. Pts also received 12 doses of prophylactic IT chemotherapy. Results: Between 2/2018 and 1/2023, 54 pts were with newly diagnosed Ph+ ALL were treated. Baseline characteristics are shown in the table. Among 35 pts evaluable for hematologic response, 23 (97%) achieved CR/CRi; 1 pt had early death. Among 48 pts evaluable for molecular response, 34 (71%) achieved CMR after 1 cycle, and 43 (90%) achieved CMR at any time. After 2 weeks of therapy, 18/35 tested pts (51%) achieved CMR in the peripheral blood. 34/38 tested pts (89%) achieved MRD negativity by next-generation sequencing at a level of 10 -6 . Four of these pts who were MRD-negative by NGS had detectable low-level BCR:ABL1 transcripts by PCR at the same time (ranging from 0.01% to 0.05%). The median follow-up is 16 months (range, 1-55 months). Three patients relapsed after a median of 9 months of remission (range, 8-23 months), 1 in bone marrow with new E225V mutation and 2 extramedullary-only. Three pts have died (1 from intracranial hemorrhage, 1 from post-procedural hemorrhage, and 1 from brain aneurysm). There have been no leukemia-related deaths, the estimated 2-year EFS and OS are both 90%. Only 1 pt underwent SCT in first remission; this pt was transplanted due to persistently low-level BCR:ABL1 positivity. Among the 47 pts in ongoing remission without SCT, the median duration of response is 15 months. Most side effects were grade 1-2 and were consistent with the known toxicity profile of the two agents. Ponatinib was discontinued in 2 patients due to possibly related adverse events (CVA and coronary stenosis in 1 pt each). Conclusions: The chemotherapy-free combination of ponatinib and blinatumomab is safe and effective in newly diagnosed Ph+ ALL, with high rates of MRD negativity. Encouraging duration of remission and OS has been observed without the need for SCT. Clinical trial information: NCT03263572 . [Table: see text]
Evaluating depth of disparities in relation to relative survival rates: Analysis of SEER data.
Authors: Alma Habib, Ying Huang, Electra D. Paskett, Srinivas S. Devarakonda, James L. Fisher, Adam Kittai
Journal: Journal of Clinical Oncology (2023)

6602 Background: Prior studies have identified widening survival disparities between Black vs White patients (pts) in solid tumors with higher 5-year relative survival rates (RSR), a surrogate for higher amenability to treatment (Tehranifar et al., 2009). Given major advancements in treatment for hematologic malignancies leading to higher RSR, we sought to evaluate whether disparities worsened with higher RSR, especially among Black pts compared to White pts, in the modern era of therapy. We hypothesized that racial disparities would be larger in malignancies with higher amenability, as measured by 5-year RSR. Methods: We identified first hematologic malignancies among pts ages ≥18 years diagnosed between 2009-2019 in a collection of 17 Surveillance, Epidemiology and End Results (SEER) Program registries. We treated RSR as a continuous variable. Cox proportional-hazards model was used to correlate RSR and race with overall survival (OS) controlling for other pt characteristics. The interaction between RSR and race was included in the model to test if the racial effect on OS differed at various RSR levels. Results: We identified 363,340 pts who met inclusion criteria. Median age was 66 years and 55% were male. 82% were White and 10% Black. With a median follow-up of 48 months (mos), median RSR was 68.2% and median OS was 101 mos (95% CI 100-102 mos). Black pts had a lower median RSR than White pts, 63.8% vs 68.9%, and lower median OS, 90 mos (95% CI 87-93 mos) vs 99 mos (95% CI 98-100 mos). On univariable analysis, all variables were statistically significant given the large sample size. On multivariable analysis (MVA), Black pts had a higher risk of death than White pts. The interaction between 5-year RSR and race was highly significant (p=&lt;0.01, not shown in Table), as indicated by slightly increasing hazard ratios (HRs) reflecting Black-White survival differences with increasing RSR level (i.e., as RSR increased, Black pts had slightly worse OS than White pts) (Table). Conclusions: We hypothesized that with increasing RSR, Black-White disparities might increase, as all effective therapies which contribute to improved RSR might not be equitably available to all populations. We observed that statistically significant disparities were present across RSR levels and increased only minimally for those with hematologic malignancies with higher RSR. In conclusion, disparities are prevalent in hematologic malignancies despite the degree of amenability to treatment. [Table: see text]
Anticoagulation for portal vein thrombosis in patients with hepatocellular carcinoma: A retrospective observational study.
Authors: Kais Antonios, Bana Antonios, Kadhim Al-Banaa, Mohammad Muhsin Chisti
Journal: Journal of Clinical Oncology (2023)

e16212 Background: Portal vein thrombosis (PVT) occurs in 10-40% of patients with hepatocellular carcinoma (HCC). Advanced imaging modalities, such as MRI, can differentiate between bland PVT and tumor thrombus, and help determine the need for anticoagulation (AC). Our study aims to assess the use of AC in patients with HCC and concomitant PVT. Methods: We conducted a retrospective observational study at eight hospitals in a community healthcare system in southeast Michigan. Patients with a combined diagnosis of HCC and PVT were identified between August 2016 and September 2022. Demographics, clinical characteristics, use of AC, type of thrombus, and median survival were collected through chart review. Results: A total of 122 patients were diagnosed with HCC and PVT (17 patients were lost to follow-up). The median age at diagnosis was 72.7 years and 77.1% of patients were male. Majority (66.6%) of patients were white. Underlying cirrhosis was present in 85.7% of patients, of which 41% was due to HCV infection. Around half of the patients had a Child-Pugh Class-B at diagnosis. AC was started in 46% of patients, with apixaban being the most commonly used agent (56%). Imaging results in the AC group confirmed that 52% of patients had a tumor thrombus. Of all the patients started on AC, 25% had bleeding complications. Overall, death occurred in 52.1% of patients in the AC group compared to 57.9% of patients who did not receive AC. Median survival was 6 months in both groups (p=0.7). Using cox-proportional hazards model, there was no difference observed in overall survival between patients who received AC and patients who did not (HR 0.91, 95% CI 0.54-1.53, p=0.72). Conclusions: In this retrospective review of patients with HCC and PVT, no difference in survival was observed between patients who received AC and patients who did not receive AC. Further randomized prospective data are needed to guide management in this high-risk patient group. [Table: see text]
Effect of UBR7 deficiency on glycolysis and PDAC resistance to gemcitabine by promoting PRMT5 stability.
Authors: Lei Bi, Miaoqing Zhao, Kun Ru, Bo Tang, Yunshan Wang
Journal: Journal of Clinical Oncology (2023)

e16265 Background: Pancreatic ductal adenocarcinoma (PDAC) is a common malignant tumor of the digestive tract. Although gemcitabine and other therapeutic agents are effective in patients with advanced and metastatic pancreatic cancer, drug resistance has severely limited their use. However, the mechanisms of gemcitabine resistance in pancreatic cancer are poorly understood. Methods: In this study, ATAC-seq, ChIP-seq, and RNA-seq were performed to compare chromatin accessibility and gene expression in a patient-derived tumor xenograft (PDX) model of pancreatic cancer with or without gemcitabine resistance. Results: Analyzing these sequencing data, we found a dramatic change in chromatin accessibility in the PDX model of gemcitabine-resistant tissues and identified a key gene, UBR7, which plays an important role in mediating gemcitabine resistance. Further research found that depletion of UBR7 significantly increased pancreatic carcinogenesis and the immunosuppressive microenvironment. Mechanistically, depleted UBR7 increased the stability of PRMT5, thereby promoting glycolysis in pancreatic cancer cells. Finally, an inhibitor that blocks PRMT5 (DS-437) significantly reduced gemcitabine resistance in pancreatic cancer caused by UBR7 depletion. Conclusions: In conclusion, our results indicated that the UBR7-PRMT5 axis is a key metabolic regulator of PDAC and a promising target for the clinical treatment of gemcitabine resistance in PDAC.
Cost of breast cancer screening in the USA: Comparison of current practice, advocated guidelines, and a personalized risk-based approach.
Authors: Kimberly Badal, James Staib, Jeffrey Tice, Mi-Ok Kim, Martin Eklund, Stacey DaCosta Byfield, Kierstin Catlett, Leslie Wilson, Liz Maffey, Rashna Soonavala, Allison Stover-Fiscalini, Laura Esserman
Journal: Journal of Clinical Oncology (2023)

e18917 Background: Several clinical trials are comparing the safety and efficacy of risk-based and age-based breast cancer screening. This study aimed to estimate the aggregate yearly cost of screening in the USA for 2019 to 2021 and to project cost of four strategies: annual, biennial, hybrid, and the WISDOM (Women Informed to Screen Depending on Measures of risk) clinical trial’s risk-based strategy. An assessment of screening costs under different strategies can inform policy decisions. Methods: Total cost was estimated for each strategy by summing screening and recall cost for eligible women from a national payer perspective. Data from the FDA Mammography Quality Standards Act and Program was used to estimate the number of screening mammograms in 2019 to 2021. Data from the Optum Labs Data Warehouse (OLDW) was used to estimate utilization of 2D and 3D mammograms, MRI and mammogram costs, recall costs and rates. OLDW contains longitudinal de-identified administrative, medical, and pharmacy claims for over 200 million commercial and Medicare Advantage (MA) enrollees and patients. Study subjects were continuously enrolled for approximately three years to capture all encounters. Medicare Advantage claims were used to approximate public payer costs and rates. We assumed 100% adherence to all strategies. The risk-based strategy used a cost of $270 for genetic testing and risk assessment. Probabilistic sensitivity analysis was used to estimate uncertainty in the estimated aggregate cost. One-way deterministic sensitivity analysis was used to determine the impact of each input on the aggregate cost. Results: Median mammogram costs ranged from $139-$360, MRI costs ranged from $545-$2,439, while recall rates ranged from 9.2%-20.9%. The annual cost of screening 50% of eligible women in 2019 was $11.5B ($10.37-13.94B) and cost $77,824 per breast cancer detected. The estimated yearly aggregate cost of screening 100% of eligible women was: $26.71B ($24.61-32.82B) for annual; $18.09B ($16.03-21.16B) for hybrid; $7.57B ($6.97-9.29B) for biennial; and $9.60B ($8.88-11.70B) for risk-based strategies. The estimated average cost per woman screened until 74 years was: $22,315 for annual; $16,552 for hybrid; $4,133 for biennial; and $6,878 for risk-based. The yearly aggregate cost of screening was most sensitive to variations in commercial 3D mammography cost. Conclusions: Biennial and risk-based screening can reduce cost substantially. Risk-based screening reduced cost even with the cost of population genetic testing included while maintaining intensive screening for the highest-risk women. The resources saved can be used to improve screening for women at high-risk of fast-growing disease who are often identified between screens and for improving overall adherence.
The efficacy and safety of toripalimab combined with sorafenib for unresectable hepatocellular carcinoma: An open-label, prospective, single-arm phase II study.
Authors: Xin-Rong Yang, Jian-Wen Cheng, Suiyi Wu, Bo Hu, Shuang-Jian Qiu, Hui-Chuan Sun, Jia Fan, Jian Zhou
Journal: Journal of Clinical Oncology (2023)

e16184 Background: Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage, leaving patients ineligible for surgery. Sorafenib is a first-line therapy, but disease progression still occurs in most patients within a year. Toripalimab, an immune checkpoint inhibitor has demonstrated promising efficacy and safety in various solid tumors, and its combination with Sorafenib may alter outcomes in HCC patients. This study aims to assess the safety and efficacy of Toripalimab plus Sorafenib for the treatment of advanced HCC. Methods: This is a single-arm, open-label, prospective phase II clinical trial (NCT04926532) for patients with unresectable HCC. Participants receive Toripalimab (240mg, iv, d1) and Sorafenib (400mg, bid, po, d1-21) every 3 weeks until disease progression or unacceptable toxicity occurs. The primary endpoints are objective response rate (ORR) evaluated with RECIST v1.1 and safety. Secondary endpoints include progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and duration of response (DOR). Exploratory endpoints comprise monitoring indicators for the efficacy and sensitivity of immunotherapy drugs. Results: As of January 17, 2023, 28 patients were enrolled, with a median age of 59.8 years and 85.7% were male. All patients had Child-Pugh A classification. The median follow-up time was 14.7 months (2.3-31.3). The distribution of patients by CNLC stage was as follows: Ib/IIa/IIb/IIIa/IIIb stage were 25.0%, 17.9%, 25.0%, and 32.1%, respectively. Among all patients, 6 (21.4%) had distant metastasis, 7 (25.0%) had portal vein tumor thrombus (PVTT), and 3 (10.7%) had hepatic vein invasion. The ORR was 35.7% and DCR was 71.4%. Of the 28 patients, 3 (10.7%) achieved complete response (CR), and 7 (25.0%) achieved partial response (PR). The median DOR was 2.7 months (95% CI: 0.9-16.9). The median PFS was 4.8 months (95% CI: 3.1-18.9), and the median OS was not reached (95% CI: NA-NA). 6 patients (21.4%) underwent surgical resection, and 3 of them (50.0%) experienced postoperative recurrence. The median PFS of patients who underwent surgery was 20.4 months (95% CI: 12.6-NA). 6 patients (21.4%) withdrew due to adverse events (AEs). Treatment-related adverse events (TRAEs) occurred in 26/28 patients (92.9%). Grade 1-2 TRAEs occurred in 10/28 patients (35.7%), Grade 3 TRAEs occurred in 11/28 patients (39.3%), and no grade 4-5 TRAEs were observed. This study is currently ongoing. Conclusions: Toripalimab combined with Sorafenib demonstrated encouraging efficacy and tolerable toxicity as a first-line option for patients with unresectable HCC, with some patients achieving tumor downstaging and surgical resection. This combination could be considered an optional regimen for the first-line treatment of unresectable HCC. Clinical trial information: NCT04926532 .
Early results from CASCARA: A phase 2 study of cabazitaxel/carboplatin plus abiraterone in high-volume metastatic castrate-sensitive prostate cancer (mCSPC).
Authors: Charles J. Ryan, Qing Cao, Andre Luiz De Souza, David James VanderWeele, Alan Haruo Bryce, William Kevin Kelly, Gautam Gopalji Jha, Pedro C. Barata, A. Oliver Sartor, Walter Michael Stadler, Mallika Sachdev Dhawan, Alicia K. Morgans, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2023)

5071 Background: Best treatment of mCSPC involves doublet therapy (ADT + novel hormonal agent) or triplet therapy (ADT + novel hormone + docetaxel); however, opportunity remains for further improvement. Studies show that homologous recombination repair (HRR) gene mutations are enriched in metastatic prostate cancer, and may portend resistance to docetaxel. CASCARA tested quadruplet therapy (ADT + cabazitaxel/carboplatin + abiraterone) in high-volume mCSPC, aiming to enhance PSA responses and decrease progression at 1 year. Methods: This phase 2 study enrolled 61 mCSPC patients with high-volume disease who received ADT plus cabazitaxel (20 mg/m 2 q21d x 6) and carboplatin (AUC=4 q21d x 6) followed by abiraterone (1000 mg, plus prednisone 5 mg). Primary endpoint was freedom from PSA/radiographic progression at 1 year. Other endpoints included PSA 50 response, freedom from PSA progression, and safety. Archival biopsies were retrospectively evaluated for HRR ( BRCA1/2, ATM, CHEK2, CDK12, BRIP1, RAD51B) mutations at a CLIA-certified lab. A sample size of 61 was determined using a Simon two-stage design (stage 1: 32 men, stage 2: 29 men) with a null hypothesis of a 1-year PSA/radiographic progression-free rate of 0.80 against a one-sided alternative of 0.92. Results: From 11/2019 to 06/2022, 61 men enrolled at 7 sites. Median age was 64 (range, 45–76) years; 21% were African American. Median baseline PSA was 8.9 (range, 0.1–1021) ng/mL. 44% of men had ECOG=1. 91% had Gleason sum 8–10. Prevalence of DNA alterations (50 evaluable pts) was 18% for HRR mutations, 38% for TP53 muts, 22% for ERG fusions, 10% for SPOP muts. Freedom from PSA/radiographic progression at 1 year was 77% (95% CI, 63–87%), and freedom from PSA progression at 1 year was 81% (95% CI, 67–90%). The PSA 50 rate response was 97%. PSA ≤0.2 ng/mL at month-7, a surrogate for survival in other mCSPC studies, was 61%; PSA ≤4 ng/mL at month-7 was 82%. Outcomes according to mutation status are shown. AEs included 7% grade (Gr)-3/4 myelosuppression, 8% Gr-3/4 infections, 10% Gr-3 GI disorders, and 3% Gr-3 fatigue. There were 4 treatment-related discontinuations. Conclusions: Quadruplet therapy with ADT + cabazitaxel/carboplatin + abiraterone was well tolerated. At 1 year, 77% of pts were progression-free. PSA ≤0.2 ng/mL at month-7 was 61%, exceeding the historical month-7 PSA ≤0.2 ng/mL rate of 45% in CHAARTED–docetaxel arm. Further exploration of this quadruplet strategy in randomized phase III studies is warranted. Clinical trial information: NCT03934840 . [Table: see text]